Immediate release naltrexone composition comprising between about 0.01 and about 10 mg of naltrexone was specifically designed to enhance immunomodulation and anticancer properties with fewer side effects then existing therapies. Clinical Studies have shown that to have an immunomodulating effect naltreoxone must be in an Immediate release formulation and not as timed release or slow release. The Immediate release naltrexone composition comprising between about 0.01 and about 10 mg of naltrexone not only inhibit angiogenesis, but also induce apoptosis and growth arrest in resistant cancer cells. They also prevent the adhesion of cancer cells to bone marrow stromal cells and thereby inhibit the enhanced secretion of migratory factors, such as interleukin (IL)-6, TNF-α, and vascular endothelial growth factor.
Where high dose naltrexone and slow release naltrexone between 0.01 mg and 10 mg and an Immediate release naltrexone composition comprises between about 0.01 mg and about 10 mg of naltrexone share commonality in categories of genes and are considered the same drug, the difference in dosing and delivery method of the Immediate release naltrexone of the invention produces a difference in the overall response of the immune system.
For a wide range of drugs, oral dosage forms such as tablets are clearly the preferred form of delivery. This is due to a high level of patient acceptability and compliance (because they provide an accurate dosage and are easy to administer) as well as advantageous characteristics during and after manufacture, such as they typically show satisfactory physical and chemical stability, are convenient for packing, shipping and administering and offer advantages in manufacturing speed and cost.
However, oral dosage forms need carefully designed disintegration characteristics to achieve the desired bioavailability for the incorporated drug, i.e. dissolution must precede absorption, in case of immediate release tablets should disintegrate rapidly after ingestion in order to facilitate dissolution of the drug. Moreover, the drug loading of conventional tablet formulations is often limited due to potential gastrointestinal irritation (caused by locally high concentration) and/or patient compliance (which limits size and shape to achieve easy swallowing). The Naltrexone formulation described which comprises between 0.05 mg and 10 mg requires immediate onset of action. To meet this requirement immediate release dosage forms have been formulated to disintegrate rapidly after administration with enhanced rate of dissolution.
To accomplish this goal tablets were developed using superdisintegrants such as cross linked polyvinylpyrrolidone or crospovidone (Polyplasdone), modified starches such as sodium starch glycolate (e.g. Primogel, Explotab), soy polysaccharides, cross linked alginic acid, gellan gum, xanthan gum, calcium silicates, ion exchange resins such as INDION 414 and modified celluloses such as carboxymethylcellulose (Croscarmellose sodium). These superdisintegrants provide instantaneous disintegration of tablet after administration in stomach. In the case of immediate release liquid dosage forms and parenteral dosage forms the naltrexone formulation described can be a suspension with typical dispersion agents such as hydroxypropyl methylcellulose and AOT (dioctylsulfosuccinate).
Immediate release tablets are those which disintegrate rapidly and dissolve to release the medicaments. Immediate release may be provided for by way of an appropriate pharmaceutically acceptable diluent or carrier, which diluent or carrier does not prolong, to an appreciable extent, the rate of drug release and/or absorption. An Immediate release formulation excludes formulations which are adapted to provide for “modified”, “controlled”, “sustained”, “prolonged”, “extended” or “delayed” release of drug. The immediate-release tablets and capsules release the active ingredient within a small period of time, typically less than 30 minutes.
There is a difference in the cell patterns of genes that are altered by the treatment of Immediate release naltrexone of the invention versus high dose naltrexone and slow release low dose naltrexone between 0.01 mg and 10 mg. The differences are important because an Immediate release naltrexone composition which comprises between about 0.01 and about 10 mg of naltrexone acts as an immunomodulator. Since the Immediate release naltrexone described blocks the opiate receptors only for a few hours before it is naturally excreted, what results is a rebound effect; in which both the production and utilization of met (5) enkelphine opiate growth factor are increased. Once the Immediate release naltrexone has been metabolized, the elevated endorphins produced as a result of the rebound effect can now interact with the more-sensitive and more-plentiful receptors and assist in regulating cell growth and immunity. This rebound effect is not observed with either high dose naltrexone or slow release naltrexone. It is the rebound immunomodulatory effect that effects the treatment of treating patients suffering from human immunodeficiency virus (HIV) acquired immune deficiency syndrome (AIDS), Autoimmune Disease, Opportunistic Infections, Cancer, Inflammation, and Neurodegenerative Diseases (“Younger J, Clin. Rheumatol. 2014; 33(4): 451-459. PMCID).
The immune system protects the body against infectious agents, including bacteria, viruses, fungi, and parasites. In addition, the immune system protects against cancer, as well as disease states that result from immune imbalances and opportunistic infections. Stimulation of the immune system by pharmaceuticals is an important approach to the prevention and treatment of diseases associated with immune suppressed states.
The response by the immune system to an immunogen may be depressed as a consequence of certain diseases or pathological conditions. For example, patients infected with the human immunodeficiency virus (HIV-1) may develop acquired immune deficiency syndrome (AIDS) or AIDS related complex (ARC), and thus have depressed immune responses. In addition to patients with HIV/AIDS patients undergoing cancer therapy, suffering from opportunistic infection or inflammatory diseases have a depressed immune system either due to the diseases or caused by the immunosuppressing drug used in the treatment of cancer, autoimmune disease and HIV/AIDS.
Patients with depressed immune systems are more susceptible to pathological infections or malignancies against which a normal immune system would have otherwise provided sufficient protection. Other such immunocompromised individuals include patients with opportunistic infections, autoimmune diseases, cancer, or undergoing X-rays, radiation treatment, surgery, or chemotherapy treatment.
Current treatments used to prevent the development of immunodeficiency in individuals with viral infections, HIV for example, usually involve administration of compounds that inhibit viral DNA synthesis thereby slowing onset of viral-related immunosuppression.
More recent treatments against HIV include administration of protease inhibitors such as saquinovir, nefinavir, ritonavir and indinavir. Cytokine therapy is also used in the treatment of AIDS patients, with research groups having demonstrated efficacy of interleukin-2 (IL2) in elevating the CD4 T-cell subset in HIV positive patients (Kovacs, et al., N. Engl. J. Med., 1996; 335: 1350-1356). Reports have detailed that IL2 can also increase CD8 T-cell count (Schmitz, et al., Science, 1999; 283: 857-860). Unfortunately, the use of IL2 is normally accompanied by major toxicity (Davey, et al., JAMA, 2000; 284: 183-189). Many of these same drugs are used to treat cancer, autoimmune disease and neurodegenerative diseases.
Nevertheless, given the potential promise of these therapies directed toward anti-retroviral effects, none have proven to be totally effective in treating or preventing development of AIDS. In addition, many of these compounds cause adverse side effects including “black box” warnings of the risk of hematological, toxicity, myopathy, lactic acidosis hepatic decompensating, lactic acidosis, severe hepatomegaly with steatosis and exacerbation of hepatitis B, Drug interaction leading to serious and life threating reactions, including sedative hypnotics, etc; hepatic metabolism, skin reactions low platelet count, diarrhea, nausea, renal toxicity, and bone marrow cytopenia. Numerous clinical studies with low dose naltrexone in normal volunteers, HIV positive, multiple sclerosis, autism, fibromyalgia, diabetes, and cancer patients showed no major toxicity.
Current treatments used to prevent the development of immunodeficiency in individuals with autoimmune disease, Crohn's Disease, multiple sclerosis and cancer, for example, usually involve administration of compounds that slow or suppress the immune system response in an attempt to stop the inflammation involved in the autoimmune attack are called immunosuppressive medications. These drugs include corticosteroids (prednisone), methotrexate, cyclophosphamide, azathioprine, and cyclosporin. Unfortunately, these medications also suppress the ability of the immune system to fight infection and have other potentially serious side effects.
More recent treatments against autoimmune diseases and cancer include administration of glucocorticoids, cytostatics are nitrogen mustards (cyclophosphamide), nitrosoureas, platinum compounds, interferons and TNF binding proteins.
Nevertheless, given the potential promise of these therapies directed toward autoimmune disease and cancer, none have proven to be totally effective in treating or preventing development of autoimmune disease or cancer. In addition, many of these compounds cause adverse side effects including “black box” warnings of the risk of hematological, toxicity, myopathy, lactic acidosis hepatic decompensating, lactic acidosis, severe hepatomegaly with steatosis and exacerbation of hepatitis B, Drug interaction leading to serious and life threating reactions, including sedative hypnotics, etc; hepatic metabolism, skin reactions low platelet count, diarrhea, nausea, renal toxicity, and bone marrow cytopenia. Numerous clinical studies with Immediate release naltrexone dosed between 0.01 mg and 10 mg in normal volunteers, HIV positive, multiple sclerosis, autism, fibromyalgia, diabetes, and cancer patients showed no major toxicity.
Thus, there exists a need in the art for improved methods of stimulating a sustained immune system response in patients in need of such treatment, such as patients include those with compromised immune system responses (e.g. the potential to develop compromised immune system responses HIV-infected (e.g. AIDS patients), opportunistic infections, autoimmune disease, cancer, cardio vascular disease, inflammatory diseases, and neurodegenerative diseases.
It is therefore unexpected that an Immediate release naltrexone composition comprising between about 0.01 mg and about 10 mg of naltrexone could be used in methods of treatment useful in producing a sustained immune response in a patient comprising administering the active agents on dosage schedule to a patient in need of such treatment.
It is also surprising that an Immediate release naltrexone composition comprising between about 0.01 mg and about 10 mg of naltrexone is effective in promoting a sustained cell increase in immune system response including sustained cell levels.
The present invention provides for, inter alia, methods of treatment useful for inducing a sustained immune system response in an immunocompromised patient in need of such treatment wherein the method comprises administering to the patient an Immediate release naltrexone composition comprising between about 0.01 mg and about 10 mg of naltrexone, either alone, combined, or in further combination with other compounds useful for increasing immune system response, including vaccines. In this context, “immunocompromised” refers to any reduction in T-cell number or function.
The present invention also provides for, inter alia, methods of treatment useful for inducing a sustained immune system response in an HIV-infected patient, wherein the method comprises administering to the HIV-infected patient an Immediate release naltrexone composition comprising between about 0.01 mg and about 10 mg of naltrexone, either alone, combined, or in further combination with other compounds useful for slowing the progression of HIV proliferation or HIV-associated infections, such as abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir disoproxil fumarate, zidovudine (AZT), atazanivir, darunavir, fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir, tipranavir, enfuviritide, maraviroc, dolutegravir, elvitegravir, raltegravir, cobicistat, efavirenz, nevirapine, etravirine and rilpivine. Combination HIV therapies are also included to be administered with the naltrexone formulation described such as abacavir and lamivudine; abacavir, dolutegravir and lamivudine; abacavir lamivudine and zidovudine; atazanavir and cobicistat; darunavir and cobicistat; efavirenz, emtricitabine and tenofovir disoproxil fumerate; elvitegravir, cobicistat, emtricitabine, tenofovir alafenamide fumerate; elvitegravir, cobicistat, emtricitabine and tenofovir disoproxil fumerate; emtricitabine, rilpivirine and tenofovir alafenamide; emtricitabine, rilpivirine and tenofovir disoproxil fumerate; emtricitabine and tenofovir alafenamide; emtricitabine and tenofovir disoproxil fumerate; lamivudine and zidovudine; and lopinavir and ritonavir. Additionally, cytokines such as G-CSF, IL-11, IL-12, IL-2; and gamma interferon and antibiotics or other drugs used for the treatment or prevention of infections in HIV-infected patients. Administration to such patients comprises a single oral, liquid or cream dose of an Immediate release naltrexone composition comprising between about 0.01 mg to about 10 mg of naltrexone. It is known that for naltrexone blocks the opiate receptor, but the effect on the immune system only occurs when the opiate receptor is blocked for a short period of time which requires the naltrexone be an Immediate release naltrexone composition comprising between about 0.01 mg and about 10 mg of naltrexone to have an immunomodulatory effect.
The Immediate release naltrexone composition comprising between about 0.01 mg and about 10 mg of naltrexone was specifically designed to enhance immunomodulation and anticancer properties but with less side effects. (Mohammad A. Seifrabiei, Mohammad Abbasi, Ali Montazeri, Fatemeh Shahnazari and Arash Pooya American Journal of Applied Sciences 5(7): 872-875, 2008.)
Clinical Studies reveal that an Immediate release naltrexone composition comprising between about 0.01 and about 10 mg of naltrexone not only inhibit angiogenesis but also induce apoptosis and growth arrest in resistant cancer cells. They also prevent the adhesion of cancer cells to bone marrow stromal cells and thereby inhibit the enhanced secretion of migratory factors, such as interleukin (IL)-6, TNF-α, and vascular endothelial growth factor. In research experiments, ovarian cancer cells were treated with either water as the control or different dosing regimens of naltrexone to replicate high dose versus Immediate release dosing of naltrexone. Using the Immediate release low or short-term dosing composition of naltrexone it was observed that the growth of cancer cells was slowed; however, when a high dose of naltrexone was used, cancer cells were stimulated and grew faster.
Autoimmune disease, cancer, cardiovascular disease, inflammatory bowel disease, Musculo-skeletal disorders, metabolic disorders and neuro degenerative diseases develop when the immune system begins to dysfunction which can be caused by a number of factors. When an organism mounts an anti-self response, usually as a result of abnormalities of the afferent parts of the immune system which are involved in antigen-specific responses and chronic inflammation which can be can be triggered by cellular stress and dysfunction, such as that caused by excessive calorie consumption, environmental factors, elevated blood sugar levels, and oxidative stress. It is now clear that the destructive capacity of chronic inflammation is unprecedented among physiologic processes (Karin et al. 2006). Chronic inflammation is caused by a causative agent, non-degradable pathogens that cause persistent inflammation, infection with some types of viruses, persistent foreign bodies, overactive immune system reactions and it causes major cells involvement—macrophages, lymphocytes, plasma cells (these three are mononuclear cells), and fibroblast with primary mediators—reactive oxygen species, hydrolytic enzymes, IFN-γ and other cytokines, growth factor and long term inflammation causes the destruction of tissue, thickening and scarring of connective tissue (fibrosis), death of cells or tissues (necrosis).
Naltrexone when used in Immediate releasing composition comprising between about 0.01 mg to about 10 mg of naltrexone is an immune-modulating drug and as such has more then one mechanism of action in the treatment of immune deficiency diseases, opportunistic infections, autoimmune disease, cancer, cardio vascular disease, chronic infections, inflammatory diseases, inflammatory bowel disease, musculo-skeletal disorders, metabolic disorders and neurodegenerative diseases. As an immune-modulating drug, naltrexone has a cascade benefit effect on the immune system.
As an immunomodulatory drug, Immediate release naltrexone comprising between about 0.01 mg and about 10 mg of naltrexone works by binding for a short period of time with mu receptors. An Immediate release naltrexone composition comprising between about 0.01 mg and about 10 mg has an affinity to at least a million extremely specific delta receptors. An Immediate release naltrexone composition comprising between about 0.01 mg and about 10 mg of naltrexone has only a weak binding to only one hundred such receptors. An Immediate release naltrexone composition comprising between about 0.01 mg and about 10 mg of naltrexone blocks the mu receptor and upregulates delta receptors so the endorphins released at night binds to the delta not the mu receptors, which results in stimulation of the immune system via delta receptors and the blocking of the mu agonists for longer then 4 to 6 hours suppress the immune system.
The blocking of the mu receptor for a short period causes an increase the products of cytokines including met-enkelphine. This interaction regulates normal cell growth. If too much met-enkelphine or opiate growth fact (“OGF”) OGF is released, it slows cell growth and if too little OGF or enkephalin is released the cells proliferate in an out of control manner and have the potential to become cancer cells or overactive immune cells. If the naltrexone dose is too high, or an Immediate release dose composition comprising an amount of naltrexone higher than about 10 mg of naltrexone, then naltrexone is still bound to the opioid receptor and the met-enkephalin cannot interact with the receptor. The end result and risk of taking such compositions is that either there will be no effect or the cancer cell growth
High dose naltrexone, slow release low dose naltrexone and Immediate release naltrexone compositions comprising between about 0.01 and about 10 mg of naltrexone share commonality in categories of genes and are considered same drug except for the difference between both the type of delivery and the dose. These factors determine if naltrexone acts as a immunomodulator and is a benefit to immune comprised patients.
An Immediate release naltrexone composition comprising between about 0.01 mg and about 10 mg of naltrexone blocks opiate receptors temporarily (typically 2-4 hours), which leads to rebound increase in endogenous opioids and endorphins but especially in the production of cytokines which are critical to immune health. (“Critical Regulators of Cytokine Signaling and Immune Responses”, International Congress Series Volume 1285, November 2005, Pages 121-129)
An Immediate Release naltrexone composition comprising between about 0.01 mg and about 10 mg: increases endorphins and inhibits cell proliferation in vivo, while high dose naltrexone or slow release naltrexone decreases endorphins, promotes cell growth, Increases endorphin levels, decreased inflammatory cytokines, shift from Th1 (pro-inflammatory) to Th2 (anti-inflammatory), reduces production of TNF and begins to effect TRL4 and TRL9 within 72 hours and reduce inflammation. (Faith; Robert E.; Faith, Robert E.; Murgo, Anthony J; Good, Robert A.; Plotnikoff, Nicholas P. Cytokines: Stress and Immunity, Second Edition (Page 362).).
Parallel with OGFR function, as OGF exhibits cancer growth features similar to an Immediate release naltrexone composition comprising between about 0.01 mg and about 10 mg. But continuous 48 h exposure to naltrexone has no dramatic effect in a number of tumors, no effect on pancreatic cancer cells: MIA-PaCa2, PANC1, and BxPC3, no effect on glioma cells: T98G and U87MG, no effect on A549 (lung) and HCT116 (CRC) no effect expression of CDK Inhibitors p15, p18, p19, and p27 are not altered by Immediate release naltrexone.
Continuous exposure naltrexone in a dose between 0.01 mg and 10 mg stimulates the growth of tumors. Treatment with an Immediate release naltrexone composition comprising between about 0.01 mg and about 10 mg of naltrexone inhibit tumor growth, this is associated with the short-term blockade of opioid receptors. This blockade causes a compensatory increase in receptors; however, the result of this differs with dose. An Immediate release naltrexone composition comprising between about 0.01 mg and about 10 mg of naltrexone is associated with cell cycle responses via OGF action on p16INK4a and p21WAF1/CIPp16.
The continuous exposure to an Immediate release naltrexone composition comprising between about 0.01 mg and about 10 mg of naltrexone has a dramatic effect in the number of tumors such as pancreatic cancer cells, glioma cells, TRL9, TRL4, and T-cell productions and beta-endorphin levels. The effect on beta-endorphin levels is very important because beta-endorphin levels are reduced to ⅛ to ¼ normal levels in autoimmune related and rheumatic disease as Fibromyalgia, MS, Crohn's Disease, endometriosis, cluster headaches, chronic migraines, lupus, arthritis and gout. An Immediate release naltrexone composition comprising between about 0.01 mg and about 10 mg has been shown to increase beta-endorphines levels, which shifts the balance from Th1 to Th2 cells to decrease inflammation.
Like opiate receptors toll like receptors are present throughout the body. They are part of the bodies first line defense mechanism against invading pathogens (such as viruses, parasites, bacteria, protozoae etc.). Basically, these receptors spot “non-human” proteins and start a defense against them. We found that not all the cytokine expressions by the macrophage were decreased while TLR9 was downregulated, IL-12, TNF-alpha, IFN-gamma and IL-1 beta expressions were significantly decreased, but IL-6, IFN-beta and IL-10 expressions were not affected. Interestingly, the level of IFN-alpha was even increased. This alteration of cytokines produced by TLR9-downregulated APCs upon CpG ODN stimulation might indicate that the role of CpG DNA is more complicated in the pathogenesis and prevention of diseases. In addition, LR2 and TLR9 and co-stimulation of TLRs have been shown to induce HIV replication. Together these results underscore the importance of TLRs in bacterial Ag- and CpG DNA-induced HIV-LTR trans-activation and HIV replication. These observations may be important in understanding the role of the innate immune system and the molecular mechanisms involved in the increased HIV replication and HIV disease progression associated with multiple opportunistic infections. Based on the present evidence, it is likely that TRL9-activated immune responses to the CpG motif in GEM91 were responsible for the observed increases in viral load, and that CpG motif in oligonucleotide phosphorothioates is biologically active. (J Immunol. 2003 May 15; 170(10):5159-64.) Toll-like receptor 2 (TLR2) and TLR9 signaling results in HIV-long terminal repeat trans-activation and HIV replication in HIV-1 transgenic mouse spleen cells: implications of simultaneous activation of TLRs on HIV replication.) This supports the premise that low dose naltrexone is useful in the treatment of HIV/AIDS. The connection between an Immediate release naltrexone composition comprising between about 0.01 mg and about 10 mg of naltrexone as effective the regulations of TRL9 in the stopping of the progression of HIV/AIDS and opportunistic infections has not been previously described. (Plotnikoff N P, Wybran J: Methionine-enkephalin Shows Promise in Reducing HIV in Blood. Ann N.Y. Acad Sci. 1987; 496:108-14.)
It is thought that many autoimmune diseases are caused by feedback loops. For example, chronic infection can cause huge inflammatory response (such as Epstein Barr, Crohn's Disease, IBS, fibromyalgia) and the excess inflammatory response damages cells in the body in the effort to kill the infection.
During this process, the TLR-4 receptors are constantly being stimulated to fight off an infection, which does not exist, because the TLR-4 receptors are being stimulated all the time by natural parts of your blood. This, unfortunately, leads to the body ignoring real infections and the body being induced to attack healthy cells which results in the broad spectrum of autoimmune diseases.
An Immediate release naltrexone composition comprising between about 0.01 mg and about 10 mg reduces nitric oxide synthase activity, inhibits glutamate formation and microglial activity, and reduces proinflammatory cytokine and neurotoxic superoxide production. Filamin A modulates the mu opioid receptor. An Immediate release naltrexone composition comprising between about 0.01 mg and about 10 mg effect adenosine receptors involved in pain signaling and intrathecal adenosine suppresses pain.
It is via the non-opioid antagonist path that an Immediate release naltrexone composition comprising between about 0.01 and about 10 mg of naltrexone exerts its anti-inflammatory effects. Microglia are central nervous system immune cells that are activated by a wide range of triggers. Once activated, microglia produce inflammatory and excitatory factors that can cause such as pain sensitivity, fatigue, cognitive disruption, sleep disorders, mood disorders, and general malaise.
When chronically activated, the resulting pro-inflammatory cascade may become neurotoxic, causing several deleterious effects. Given the wide variety of diseases that are caused by increase inflammatory factors produced by activated microglia (e.g., pro-inflammatory cytokines, substance P, nitric oxide, and excitatory amino acids) a range of symptoms and medical outcomes could share the pathophysiological mechanism of central inflammation. Conditions such as fibromyalgia may involve chronic glial cell activation and subsequent production of pro-inflammatory factors.
The hypothesis is indirectly and partially supported by the high degree of symptomatic overlap between fibromyalgia and cytokine-induced illness. An Immediate release naltrexone composition comprising between about 0.01 and about 10 mg of naltrexone blocks the TLR-4 receptor experimentally, and in vivo. (In a test tube and also humans) Blocking these receptors causes the whole cycle to activate or re-balance and the immune system gradually return too normal. (Faith, R E, Murgo, A J, Good R A, Plotnikoff N P, 2012 Cytokines: Stress and Immunity, Second Edition).
Unfortunately, the TLR-4 receptors probably cannot “unlearn” to react to something, so the treatment with low dose naltrexone is long term and will control the symptoms after varying periods of initial treatment, depending on which set of TLR-4 receptors are malfunctioning. Crohn's patients have positive response due to the number of TLR-4 and TRL-9 receptors in the bowel and intestines. Studies have shown when patients stopped taking an Immediate release naltrexone composition comprising between about 0.01 and about 10 mg of naltrexone have seen the return of the chronic disease and symptoms and when patients resume treatment with an Immediate release naltrexone composition comprising between about 0.01 and about 10 mg the symptoms subside once again.
The central nervous system (CNS) is made up of nerves and glial cells. The function of the glia is to provide immune protection and provide defense to the CNS. Under normal conditions the glia remain in an inactivate state. They become activated readily in response to infection or injury. The most important change that happens during inflammation of the brain and spinal cord (CNS) is activation of glial cells, which explains the effectiveness of an Immediate release naltrexone composition comprising between about 0.01 and about 10 mg of naltrexone helps with neurodegenerative diseases.
When glial cells are activated they trigger the release of certain chemicals known as pro-inflammatory and neurotoxic factors. These factors include several cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin one beta (IL1β), fatty acid metabolites and free radicals such as nitric oxide and superoxide. In painful conditions such as complex regional pain and fibromyalgia and neuropathic pain, damage to the peripheral nerves shifts the glial cells to an activated state within the spinal cord.
The glial cells are made up of microglia and astrocytes. The microglia guard and protect the immune system and the astrocytes help maintain cell fluid balance which is important for the action of chemicals in the cells called neurotransmitters (needed to control nerve function). Glial cells are activated by trauma, surgery, injury, infection, and opioids. When activated, glial release pro-inflammatory and neurotoxic factors (cytokines). Opiate antagonists that block the effects of opioids and have been shown to help prevent activation of glial cells. Low dose naltrexone has been shown to inhibit the activation of glial cells. (Younger, J et al. Arthritis Rheum. 2013; 65 (2): 529-538)
Immediate release naltrexone has been shown to effect telomeres. Telomeres are inside the nucleus of a cell, our genes are arranged along twisted, double-stranded molecules of DNA called chromosomes. At the ends of the chromosomes are stretches of DNA called telomeres, which protect our genetic data, make it possible for cells to divide, and have been implicated in how we age and get cancer.
Telomeres have been compared with the plastic tips on shoelaces, because they keep chromosome ends from fraying and sticking to each other, which would destroy or scramble an organism's genetic information.
Yet, each time a cell divides, the telomeres get shorter. When telomeres get too short, the cell can no longer divide; it becomes inactive or “senescent” or it dies. This shortening process is associated with aging, cancer, and a higher risk of death.
Clinical studies have shown that telomeres are reduced in human liver tissues with age and chronic inflammation. (Telomere Reduction in Human Liver Tissues with Age and Chronic Inflammation experimental cell research 256(2):578-582⋅April 2000). Immediate release naltrexone is a proven immunomodulator that helps to reset and rebalance balance of the immune system between the cellular (Th1) and the humoral (Th2) immune systems. Immune balance is regulated through T-helper cells that produce cytokines. The Th1 lymphocytes help fight pathogens that are within cells such as viruses and among cells such as cancer through activation of interferon-gamma and macrophages. The Th2 lymphocytes target external pathogens like parasites, allergens, toxins through the activation of B-cells and antibody production therefore reducing chronic inflammation. Immediate release low dose naltrexone has been shown to regulate cytokines causing the modulation of TGF-B, leading to a reduction of Th-17, the promoter of autoimmunity. Low dose naltrexone turns off the cells growth that causes autoimmune dysfunction. Findings demonstrate that cancer cell lines that express functional TLR4 and TLR9 with possible effects on cancer progression and outcome of BCG-based (“Immunotherapy. J Biol Chem. 2013 Nov. 15; 288(46):33171-80. doi: 10.1074/jbc.M113.518175. Epub 2013 Oct. 4. Inhibition of Telomerase Recruitment and Cancer Cell Death. Nakashima M, Nandakumar J, Sullivan K D, Espinosa J M, Cech T R”).
An Immediate release naltrexone composition comprising between about 0.01 mg and about 10 mg of naltrexone has been shown in inflammatory bowel disease to halt inflammation due to the shift of Th1 to TH2 which then allow the telomeres to lengthen but at the same time Immediate release naltrexone composition will inhibit growth causing the telomeres too shorten and when the cells can no longer divide; they die. This shortening process is associated with aging, cancer, and a higher risk of death.
Research into the lengthening of telomeres to reduce inflammation indicates that telomeres lengthen in all cells including cancer cells. Immediate release naltrexone is an immunomodulator and when administered in an Immediate release composition comprising between about 0.01 mg and about 10 mg of naltrexone it will lengthen telomeres in cells and therefore reduce inflammation in patients as shown in Crohn's and inflammatory bowel disease patients. Low dose naltrexone is a proven to inhibit cells growth in cancer cells, and could assist in the slowing down of cell death and turn back the aging process by lengthening telomeres. (Telomere Extension Turns Back Aging Clock in Cultured Human Cells, Jan. 23, 2015 Stanford University Medical Center. Ramunas, E. Yakubov, J. J. Brady, S. Y. Corbel, C. Holbrook, M Brandt, J. Stein, J. G. Santiago, J. P. Cooke, H. M Blau.
The majority of the currently practiced drug treatments for autoimmune disease, cancer, cardio vascular disease, inflammatory diseases, inflammatory bowel disease, musculo-skeletal disorders, metabolic disorders and neuro degenerative diseases have significant drawbacks. The number of patients taking immunosuppressive drugs for the management of autoimmune inflammatory conditions is increasing. The general practitioner needs to be active in preventing, monitoring and managing the adverse effects of these drugs even long after the treatment has ceased. Monitoring is required because immunosuppressive drugs increase the risks of infection, malignancy, cardiovascular disease and bone marrow suppression. Apart from gastrointestinal disturbances, the nonsteroidal anti-inflammatory drugs have been shown to cause renal toxicity and therefore must be avoided particularly in lupus patients with renal involvement.
The antimalarial may cause serious retinopathy, which can occur several years after initiation of therapy. Chronic glucocorticoid therapy is associated with a number of pernicious side effects, including hypertension, excessive immunosuppression and CNS dysfunction. Immunosuppressive and cytotoxic agent a primary cause or secondary contributor in many cause bone marrow depression and lead to serious diseases, usually as a result of the formation of autoantibodies by the immune system of the organisms, which attack its own cells. Such diseases include, for example, systemic lupus erythematosus, rheumatoid arthritis, autoimmune thyroiditis, autoimmune hemolytic anemia, and certain forms of progressive liver disease. Low dose naltrexone has been shown to increase bone marrow.
Rheumatoid arthritis in its fully developed form is a symmetrical, inflammatory disease of the synovial lining of peripheral joints, which leads to destructive changes. Although arthritis is the most frequent and prominent manifestation, this is a generalized disease involving many body systems. Pathologically, rheumatoid arthritis is an inflammatory disease involving the immune system. Immune complexes (antigen/antibody) form within the joint and activate the complement system. White blood cells are then attracted into the synovial fluid. These cells phagocytose the immune complexes and in so doing release lysosomal enzymes and other chemical mediators of inflammation. Continued inflammation causes the synovium to proliferate and spread over the joint surface. The thickened synovial tissue, called pannus, releases enzymes, which erode both cartilage and bone to cause permanent damage.
Rheumatoid arthritis is treated with many of the same pharmaceutical agents used in systemic lupus. Most patients initially receive nonsteroidal anti-inflammatory drugs, sometimes together other analgesics. Where the disease is not adequately controlled with these agents, disease-modifying antirheumatic drugs, such, D-penicillamine, as well as steroids and biologic agents. Continuing therapy with any or all of the aforementioned categories of drugs can produce a variety of well-known adverse effects, and none of these drugs are significantly effective in achieving true remission of the disease in most patients.
It is known that inflammatory cells such as polymorphonuclear leukocytes have opiate receptors. The endogenous opioid, endorphin has been shown in both animal and human studies to stimulate superoxide radical production by human polymorphonuclear leukocytes via an opiate receptor. This superoxide production has been shown to be stopped by equimolar concentrations of the opiate antagonist naloxone. (B. M. Sharp et al., J. Pharm. Exp. Ther., 242(2):579-582, 1987).
As used herein, the term human immunodeficiency virus, cancer, cardio vascular disease, inflammatory diseases, inflammatory bowel disease, Musculo-skeletal disorders, metabolic disorders and neuro degenerative diseases refers the daily administration of a low dose naltrexone composition comprising between about 0.01 and about 10 mg of naltrexone has been shown to any disease state or condition associated with the shortening of telomerase causing cell death chronic inflammation and immune dysfunction.